Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancer progression to castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy (ADT) highlights critical resistance mechanisms.
• The androgen receptor (AR) signaling pathway is central to prostate cancer development and CRPC.
• Metabolic reprogramming and aberrant AR signaling drive CRPC.

Purpose of the Study:

• To elucidate the multifaceted resistance mechanisms underlying CRPC persistence.
• To explore the role of AR signaling adaptation and tumor heterogeneity in treatment resistance.
• To review current and emerging therapeutic strategies for overcoming CRPC.

Main Methods:

• Review of current literature on CRPC resistance mechanisms.
• Analysis of AR signaling pathway adaptations (amplification, mutations, splice variants, alternative activation).
• Integration of findings from single-cell and spatial technologies on tumor heterogeneity and lineage plasticity.

Main Results:

• AR signaling adapts through genetic alterations (amplification, mutations) and non-genetic mechanisms (cytokine activation) to maintain activity in low-androgen environments.
• Tumor heterogeneity, somatic alterations (e.g., PTEN loss), and pathway crosstalk (e.g., PI3K/AKT) contribute to CRPC resistance.
• Emerging therapies targeting CYP11A1, AR N-terminal domain, and bipolar androgen therapy show clinical promise.

Conclusions:

• Effective CRPC treatment necessitates cotargeting androgen/AR pathways and suppressing lineage plasticity.
• Dynamic monitoring and precision interventions are crucial for overcoming CRPC resistance.
• Understanding tumor heterogeneity and adaptive resistance mechanisms is key for future therapeutic development.